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Metabolic Regulation of Ferroptosis in Cancer

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Metabolic Regulation of Ferroptosis in Cancer biology Review Metabolic Regulation of Ferroptosis in Cancer Min Ji Kim 1,2,† , Greg Jiho Yun 1,2,† and Sung Eun Kim 1,2,* 1 Department of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul 305-350, Korea; [email protected] (M.J.K.); [email protected] (G.J.Y.) 2 Department of Integrated Biomedical and Life Sciences, College of Health Sciences, Korea University, Seoul 305-350, Korea * Correspondence: [email protected]; Tel.: +82-2-3290-5647 † These authors contributed equally to this work as co-first authors. Simple Summary: Ferroptosis is a recently defined nonapoptotic form of cell death that is associated with various human diseases, including cancer. As ferroptosis is caused by an overdose of lipid peroxidation resulting from dysregulation of the cellular antioxidant system, it is inherently closely associated with cellular metabolism. Here, we provide an updated review of the recent studies that have shown mechanisms of metabolic regulation of ferroptosis in the context of cancer. Abstract: Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer. Keywords: ferroptosis; iron metabolism; cyst(e)ine metabolism; SLC7A11; glutathione metabolism; Citation: Kim, M.J.; Yun, G.J.; Kim, GPX4; lipid peroxidation; reactive oxygen species S.E. Metabolic Regulation of Ferroptosis in Cancer. Biology 2021, 10, 83. https://doi.org/10.3390/ biology10020083 1. Introduction Academic Editor: Annalisa Pinsino “Every true story ends in death” are the words of Ernest Hemingway. Cell death is an Received: 29 December 2020 important aspect of mammalian development and homeostasis and is tightly integrated Accepted: 20 January 2021 with the physiological and pathological state of an organism. The proper orchestration Published: 22 January 2021 of cell death both spatially and temporally is critical for development and, consequently, the malfunction of cell death mechanisms can contribute to various human diseases. Publisher’s Note: MDPI stays neutral Ferroptosis is a nonapoptotic cell death mechanism characterized by iron-dependent ac- with regard to jurisdictional claims in cumulation of lipid peroxides. Importantly, ferroptosis has been implicated in neurode- published maps and institutional affil- generative diseases, kidney degeneration, and ischemic injury in multiple organs. Studies iations. using ferroptosis inhibitors have shown to be effective in ischemia/reperfusion-induced damage and in models of Huntington’s disease and Parkinson’s disease, suggesting that ferroptosis is a promising therapeutic target for the treatment of these diseases. On the other hand, the possibility of harnessing ferroptosis as a method for cancer therapy is also Copyright: © 2021 by the authors. gaining much attraction. Indeed, the original study that led to the identification of erastin, Licensee MDPI, Basel, Switzerland. a ferroptosis-inducing drug, was aimed for the selective killing of RAS-mutant cancer This article is an open access article cells [1]. Since then, multiple lines of research have suggested the important role of ferrop- distributed under the terms and tosis in cancer development and treatment. For example, ferroptosis has been suggested conditions of the Creative Commons to be a critical factor for the activities of the tumor suppressors p53, BRCA1-associated Attribution (CC BY) license (https:// protein 1 (BAP1), and fumarase [2–4]. Ferroptosis can also play a tumor-suppressive role creativecommons.org/licenses/by/ during the metastasis of cancer cells as melanoma cells in the lymph are protected from 4.0/). Biology 2021, 10, 83. https://doi.org/10.3390/biology10020083 https://www.mdpi.com/journal/biology Biology 2021, 10, 83 2 of 21 ferroptosis and, thus, can form more metastases than those in the blood [5]. Similarly, circulating tumor cells from melanoma patients have been shown to regulate lipogenesis and iron homeostasis pathways to confer resistance to ferroptosis [6]. Several types of cancer cells are susceptible to ferroptosis; thus, ferroptosis may rep- resent a novel mode of anticancer therapy. Cancer types that show high sensitivity to ferroptosis include renal cell carcinoma, diffuse large B cell lymphoma, adrenocortical carcinoma, and ovarian cancer [7–9]. Recently, it was reported that therapy-resistant or drug-tolerant cells, which are represented by a high mesenchymal state, depend on the glutathione peroxidase 4 (GPX4) pathway to evade ferroptosis, suggesting that ferroptosis induction represents an anticancer strategy for these therapy resistant cancer cells [10,11]. Similarly, platinum-tolerant or cisplatin-resistant cancer cells were also shown to exhibit increased vulnerability to ferroptosis [12,13]. This was also shown in the case of melanoma, where the dedifferentiation state of these cells was shown to correlate with increased sensi- tivity to ferroptosis [14]. The function of ferroptosis in cancer can also involve multiple cell types in the tumor microenvironment. A recent study shows that neutrophils can induce ferroptosis in glioblastoma cells by transferring myeloperoxidase-containing granules into the cancer cells [15]. Additionally, immunotherapy activated CD8+ T cells can induce fer- roptosis in cancer cells by interferon gamma-mediated downregulation of the two subunits − of system Xc , solute carrier family 7 member 11 (SLC7A11) and SLC3A2, leading to a decrease in the antioxidant capacity of cancer cells [16]. This effect can also synergize with radiotherapy through independent SLC7A11 suppression by the ataxia-telangiectasia mutated (ATM) serine/threonine kinase [17]. For the induction of ferroptosis in cancer, agents that inhibit cystine uptake via the − cystine/glutamate antiporter, system Xc , such as sulfasalazine, can induce ferropto- sis and arrest tumor growth [18]. The multikinase inhibitor sorafenib, which is used for advanced hepatocellular carcinoma, has also been shown to induce ferroptosis by − inhibiting system Xc [19]. Similarly, the systemic depletion of cyst(e)ine using an engi- neered cyst(e)ine-degrading enzyme conjugate can trigger ferroptosis and arrest tumor growth [20] and the antimalarial drug, artesunate, has also been identified as an activa- tor of ferroptosis [21]. Furthermore, ferroptosis can synergize with cisplatin to increase cytotoxicity in cancer cells [22] and radiation therapy can also synergize with ferroptosis inducers [23,24]. Although several ferroptosis-inducing agents exist, including erastin, RSL3, and ML210, further studies to enhance the pharmacokinetic properties are needed for use in clinical settings [7,25]. In essence, ferroptosis is a process that occurs through metabolic dysregulation. Ferroptosis is modulated by perturbation of lipid repair systems involving glutathione and GPX4, the enzyme that converts toxic lipid hydroperoxides to nontoxic lipid alcohols. The term ferroptosis was coined in 2012, describing the cell death induced by erastin, that inhibits the import of cystine and leads to the depletion of glutathione and inactivation of GPX4 [26]. Inactivation of GPX4 through the depletion of glutathione or through direct GPX4 inhibition results in the accumulation of lipid peroxidation that leads to cell death. Ferroptosis can be suppressed by iron chelators, lipophilic antioxidants, lipid peroxidation inhibitors, or the depletion of polyunsaturated fatty acids (PUFAs). Thus, ferroptosis is characterized by the perturbation of an intricate metabolic network which we will describe in detail in the following sections. 2. Iron Metabolism As the name ‘ferroptosis’ infers, the requirement of intracellular iron is a fundamental property of ferroptosis. As an important trace element in the human body, iron regulates numerous biological processes and, therefore, dysregulation of iron content or distribution can result in intracellular iron accumulation, which can lead to the damage of cells, tissues, and organs. Elaborate regulatory systems have evolved to maintain iron levels at sufficient yet safe concentrations in cells. Such homeostasis of iron metabolism is achieved by the coordination of iron uptake, utilization, recycling, storage, and export [27]. The iron Biology 2021, 10, x 3 of 21 Biology 2021, 10, 83 3 of 21 [27]. The iron dependency of ferroptosis was initially demonstrated by the use of iron chelatorsdependency to inhibit of ferroptosis ferroptosis. was initially Additionally, demonstrated in the same by the study, use of iron iron responsive chelators to element inhibit bindingferroptosis. protein Additionally, 2 (IRP2), a inmaster the same regulator study, of iron iron responsive metabolism, element was found binding in an protein erastin- 2 (IRP2),resistance a master screen regulatorestablishing of ironthat ferroptosis metabolism, is wasintricately found modulated in an erastin-resistance by iron metabolism. screen Perturbationestablishing thatof iron ferroptosis metabolism is intricately
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